Emerging drugs for the treatment of cutaneous T-cell lymphoma

Abstract

Introduction:

Cutaneous T cell lymphoma (CTCL) is a rare and incurable group of non-Hodgkin lymphomas that manifest as patches, plaques, tumors, and/or erythroderma in the skin. Standard skin-directed therapies for CTCL are effective in patients with indolent early-stage disease, but more advanced/refractory stage patients require systemic therapies. However, none of the treatments are considered curative and most patients suffer from relapses. Biologic therapies and immunotherapy provide novel treatment options for patients with advanced or refractory disease.

Areas covered:

This review provides a discussion of recently approved biological and novel therapeutics that are actively developed for the management of the heterogeneous group of CTCL.

Expert opinion:

Mogamulizumab and brentuximab vedotin have reached the market and are approved for the treatment of CTCL, providing valuable options. Additionally, therapies utilizing immune checkpoint inhibitors, miRNA inhibitors, and peptide inhibitors show promising results in clinical trials. Durvalumab, pembrolizumab, TTI-621, BNZ-1, and MRG-106 are several of the emerging treatments still in trials. Further combinatorial studies are needed as none of the treatments have demonstrated long-term remissions.

1. Background

Cutaneous T cell lymphoma (CTCL) is a heterogeneous group of non-Hodgkin lymphomas that manifest in the skin. Mycosis fungoides (MF) and Sézary Syndrome (SS) are the common types and make up 53% of all cutaneous lymphomas, with MF being the most common and Sézary syndrome the more advanced, aggressive, and leukemic subtype of CTCL [1,2]. In the US, the incidence of CTCL has been increasing since the 1970s but has since stabilized in 1998 with an overall age-adjusted incidence of 7.5 cases per million people [3]. Incidence is higher among Blacks than Whites and almost twice as likely in men than women [3,4]. MF is indolent and slow progressing and is characterized by erythematous patches, plaques, tumors, or rarely erythroderma. Lesions typically occur in sun-protected areas, such as breasts, buttocks, lower trunk, and groin and may evolve to infiltrative plaques and tumors [1]. The lesions can be painful, itchy, and cosmetically disfiguring, which impacts quality of life. Histologically, MF consists of proliferation of epidermotropic atypical CD4 + T lymphocytes with hyperchromatic cerebriform nuclei with an upper dermal/band-like diffuse and/or deep infiltrate interspersed with other immune cells, such as histiocytes and eosinophils [1]. SS is the rarer and more advanced subtype of CTCL, consisting of 3% of the cases and involves a leukemic component [2]. It is characterized by a triad of circulated Sézary cells, along with erythroderma and lymphadenopathy. Patients with SS often present with severe pruritus and generalized exfoliative erythroderma with keratoderma and fissures on palms and soles. Diagnosis is difficult because MF can clinically and histologically mimic benign skin conditions like vitiligo, eczema, and psoriasis. Because of this, diagnosis is delayed since topical steroids can mask characteristics and repeated biopsies are often needed, with definitive diagnosis made on average 6 years after lesions first appeared. Similarly, diagnosis of SS can be missed in the elderly because symptoms of pruritus and dry skin are attributed to advanced age. Although MF and SS have similar presentations, they are separate entities that originate from distinct memory T-cell subsets [5]. The SS expresses CCR7, L-selectin, and CD27 that supports it being a central memory T cell malignancy [5]. In contrast, MF lacks CCR7, L-selectin and CD27 expression but expresses CCR4, and CLA that supports it being a malignancy of skin resident effector memory T cells [5].

Patients who are diagnosed with early-stage MF have a good prognosis with a median survival rate of 18.3 years, whereas patients diagnosed with advanced stage MF and SS have a poor prognosis with a median survival rate of 4.7 years with an overall survival rate 78.3% [3,6]. However, there is no cure or durable remissions with 20% of patients progressing to the advanced stage. The lack of treatment success may be due to gaps in our understanding of the pathogenesis and/or heterogeneity of the disease. Established treatments including HDAC inhibitors have been developed for CTCL. Recent clinical investigations have focussed on promising targets including the CC chemokine receptor type 4 (CCR4), CD30, KIR3DL2 [CD158k], and checkpoint proteins. In this review, we will review agents that have been tested either in clinical trials or have achieved recent marketing for CTCL.

1.1. Therapeutic targets

1.1.1. miRNA

The disease is molecularly heterogeneous with diversity in its genomic landscape providing targets for potential therapies. Mutations are seen in genes related to the T cell receptor (TCR) signaling pathway or oncogenes involved in NF-κB and STAT signaling [7]. MicroRNA (miR) expression has been profiled since several miRNA classifiers have been linked to CTCL and miRNA can induce epigenetic modification in the tumorigenesis of CTCL. miRs are small noncoding RNA molecules that downregulate gene expression via epigenetic modification. It can act as an oncogene when over or under expressed because of its roles in apoptosis and cell proliferation. The most predominant miR identified is miR-155 because it is a classifier of disease versus benign states, with quantitative RT-PCR results showing that miR-155 is aberrantly expressed in all subtypes of CTCL [8]. STAT5 induces the expression of mir-155 that promotes malignant T cell proliferation. Overexpression of miR-155 is seen in skin biopsies of MF compared to benign skin disorders [9]. In contrast, miR-155 expression is low in circulating Sezary cells. Other miRs identified in CTCL are miR-21, miR-199, miR-214, and miR-486 that may relate to dysregulated signaling in the JAK/STAT pathway [9,10]. Previous studies indicate the diagnostic potential of miRs with these five miRs identified that could discriminate between malignant and benign disease [8]. No single miR is sufficient to serve as a biomarker, but sets of miRs together can form a miR signature that is present in CTCL patients. A Phase I clinical trial in CTCL has been completed, and a multicenter international phase II trial has begun for cobomarsen (antagomir to miR-155) which will be discussed later in the paper.

1.1.2. CD30

CD30 is a member of the tumor necrosis factor receptor family and is being developed as a therapeutic potential in cutaneous lymphomas. The expression activates signaling pathways that lead to anti-apoptotic and pro-survival effects. CD30 can be expressed in activated T and B lymphocytes with high positivity levels in anaplastic large cell lymphoma (ALCL) and variable positivity levels in MF [11]. Transformation of MF has been associated with CD30 expression in 40% of the cases [12]. Brentuximab vedotin is a therapeutic that targets CD30 and is now Food and Drug Administration (FDA) approved for use in cutaneous lymphomas.

1.1.3. Chemokine receptor type 4

Chemokine receptor type 4 (CCR4) has roles in leukocyte trafficking and has been associated with skin-homing T cells. CCR4 is a receptor that is normally involved in skin trafficking of type 2 helper T cells and regulatory T cells. When interacting with its ligands CCL17 and CCL22 (chemokine ligand) on dendritic cells and macrophages in the dermis, CCR4 promotes T cell migration to the skin facilitating the tumor microenvironment. CCR4 expression is upregulated in all stages of CTCL and other T cell malignancies. Studies have shown that there is an increase in CCR4 expression in tumor cells of CTCL lesions compared to normal tissue [13]. Increased number of CCR4-positive T cells was shown to correlate with a poor prognosis, hence CCR4 is an attractive target for therapeutic approaches, with one antibody-based treatment, mogamulizumab, already approved.

1.1.4. Programmed cell death protein 1 (PD1), programmed cell death ligand 1 (PD-L1), and T-cell exhaustion

In CTCL, T cells are in an overactivated state that can cause unresponsiveness to pathogens and tumor antigens leading to T cell exhaustion. In T cell exhaustion in CTCL, the constitutive PD1 expression by T cells in the CTCL tumor microenvironment (TME) was associated with the overexpression of additional inhibitory receptors, such as TIM3, LAG3, or CTLA4 that lead to impaired immune surveillance and unchecked tumor growth [14]. In CTCL skin biopsies, there are more T cells expressing PD1, CTLA4, and LAG3 in CD4+ populations and CTLA4 and LAG3 in CD8+ populations [14]. PD-L1 is expressed in the TME in CTCL, and upon ligation may elicit escape from immune surveillance. Additionally, genome-wide mRNA expression profiles show that genes for checkpoints are significantly higher expressed in advanced stages of CTCL compared to healthy controls or early stages [14]. New antibody-based therapeutic approaches target these checkpoint inhibitors to reverse T cell exhaustion.

1.1.5. CD47, SIRPα, and innate immunity

CD47 is an innate immune checkpoint that binds to the signal regulatory protein alpha (SIRPα) to suppress macrophage phagocytosis and is typically overexpressed in tumor cells. Expression of CD47 is used by macrophages to distinguish the self from the non-self. Its ligand is SIRPα that is expressed on the membrane of myeloid cells and has a role in regulating cell migration and phagocytic activity [15]. Together, they form the CD47- SIRPα signaling complex that releases ‘do not eat’ signals that inhibit macrophage-mediated phagocytosis [16]. Tumor cells exploit this ‘do not eat’ signal by expressing high levels of CD47 on their surface, therefore evading phagocytosis and promoting tumor growth [15]. TTI-621 is a novel treatment that targets CD47 by binding SIRPα.

1.1.6. Cytokines

Cytokine profiles provide information about the tumor microenvironment in MF lesions. Interleukin (IL) IL-2, IL-9, and IL-15 are pro-inflammatory cytokine interleukins. They have a common gamma chain, which is the target of IL-2 and IL-15. IL-2 has a role in the maintenance of fitness of regulatory T cells and activation induced cell death [17]. IL-15 is responsible for the maintenance of T-cell responses to invading pathogens, supporting the survival of CD8 memory T cells [17]. Studies have also shown that IL-15 is a growth factor for CTCL cells in vitro and has a causal role in the pathogenesis of CTCL [18]. IL-15 overexpression may be involved in the initial transformation, survival, and expansion of malignant T-cells in CTCL [19]. IL-2, IL-9, and IL-15 signaling pathways are also linked to the JAK3 and STAT3/5 pathways that have been linked to deregulation in CTCL [17,20,21]. IL-9 is a cytokine that is involved in tumor growth and has been shown to be expressed in MF lesions [21]. Cytokine profiles can change as the MF progresses to later stages. In the early stages, there are increases in IFN-γ, IL-12 and IL-2 [19]. There is an increase in Th2 cytokines, such as IL-4, IL-5, IL-10, and IL-13 seen in more advanced MF [19]. Increases in IL-5 and IL-10 may be responsible for the pruritus and anti-tumor response, respectively, [19]. Interleukin 13 is an autocrine factor that is also overexpressed in skin lesions of CTCL patients [22]. IL-13 can be used as a malignant tumor marker for CTCL, since it induces SS CD4 + T cell proliferation in vitro and neutralization of the pathway inhibits proliferation [22]. Because abnormal cytokines are seen in the tumor microenvironment of CTCL, they are a target of interest in therapeutic potential. Peptide antagonists that block cytokine signaling are in development and will be discussed further in this paper.

1.1.7. Killer IG-like receptor 3DL2 (KIR3DL2)

KIR3DL2, also known as CD158k, is a member of the killer cell immunoglobulin-like receptor (KIR) family that was initially identified at the surface of natural killer (NK) cells. KIR3DL2 is expressed in terms of NK cells, CD4+, and CD8 + T cells. It is upregulated in all stages of MF and particularly in SS [19,23]. KIR3DL2 is an inhibitory co-receptor on T cells and works to negatively modulate immune effector cell functions by binding to HLA Class 1 ligands [24]. Targeting of KIR3DL has seen promising efficacy in CTCL [25].

1.1.8. Chimeric Antigen Receptor (CAR)-T Therapy

CAR-T therapy redirects a polyclonal T cell population against a tumor-specific antigen. In CAR therapy, an antigen receptor is paired with an intracellular tyrosine-based activation motif from the T cell receptor [26]. This allows CD8+ cytotoxic T cells to target cell surface markers using major histocompatibility-independent activation. CAR-T therapy has shown success in B cell malignancies and is now being studied as a treatment option for T cell lymphomas. CD70, CD4, and IL-1β have been identified as potential targets. AFM-13 is a bispecific T-cell engagers (BiTE) that targets CD30 positive tumor cells and is in clinical trial for treatment of MF [27].

2. Medical need

CTCL is an incurable, disfiguring disease that deeply affects patient’s quality of life. Since there is no cure, the goal of treatment is to induce remissions and preserve quality of life in both early and advanced stages while treating the disease and symptoms. While patients with early stage disease have a good prognosis, more advanced stages and frequently relapsing disease are difficult to treat with patients requiring multiple lines of therapy [3,6]. Patients often fail treatment with a third of patients progressing to advanced stages. Due to this, there is a market for novel and promising therapeutics for the treatment of CTCL.

3. Existing treatment

A stage-based treatment is determined based on the severity of the disease. Skin-directed regimens are initiated in patients with early-stage disease. Local or total skin radiation treatment is also used to control tumor ulcers. Progressive or rapidly relapsing diseases require systemic treatment. Combination approaches are frequently used, and it is recommended that patients be treated in a multidisciplinary clinic for optimal clinical benefit. Table 1 briefly summarizes the standard existing treatments for CTCL, and detailed descriptions of these treatments are discussed below [28].

Table 1.

Summary of standard stage-based treatment regimens for CTCL.

Disease Stage	Therapy Type	Treatment
Early stage MF	Topical/skin directed	Steroids (mid-high potency)  Nitrogen Mustard 0.016% gel  Bexarotene 1% gel  Phototherapy (nbUVB, PUVA)  Local Radiation
Refractory Early Stage MF	Combination therapy	PUVA or nbUVB and IFNα  PUVA or NBUVB and bexarotene
Advanced MF/SS	Immunomodulators	Interferons  Retinoid/rexinoid  ECP
Advanced MF/SS	Biologic/targeted therapies	HDAC inhibitors  Antifolates  Mogamulizumab  Brentuximab vedotin
Advanced MF/SS	Combination therapy	IFNα and phototherapy  IFNα and retinoids  Retinoid and phototherapy  ECP and IFNα  ECP and retinoids/rexinoids

nbUVB, narrow band UVB; ECP, Extracorporeal photopheresis; HDAC, histone deacetylase; IFNα, interferon alpha.

3.1. Skin-directed treatments

Phototherapy or psoralen plus ultraviolet A (PUVA) has been a treatment for early-stage MF for 25 years and has a remission of 71.4% in patients [29]. In clinical trials of PUVA monotherapy, there was a 95% response in patients with stage IA or IB MF with complete clinical and histological clearing in 65% of the patients in all stages, demonstrating that PUVA is a safe and effective therapy for early stage MF [29]. Narrowband ultraviolet B (NBUVB) phototherapy is more effective in patients limited to patch disease with 83% receiving remission, whereas none of the patients with plaque disease achieved remission [23]. Topical steroids are used for patients with limited patch and plaque disease, whereas phototherapy is recommended for patients with more widespread patch and plaque disease. Both nitrogen mustard 0.016% gel, an alkylating agent, and bexarotene 1% gel are approved for early stage MF. Adverse events for both formulations include irritant dermatitis and pruritus [30]. Total skin electron beam therapy (TSEBT) is a radiation therapy that can be used in patients with more widespread recalcitrant cutaneous disease. Radiation therapy has a high response rate of 88% in patients with stage IB-IIIA disease, but relapse occurrence is also high [31]. Common skin-related side effects of TSEBT include erythema, telangiectasia, xerosis, and nail dystrophy [32]. Combination therapy can be utilized for skin-directed treatments as none of the skin-directed treatments are superior to one another.

3.2. Systemic treatments

Systemic biological therapies for the treatment of MF include retinoids, interferon, extracorporeal photopheresis (ECP), and histone deacetylase (HDAC) inhibitors. Interferon-alpha (IFNα) is used for the treatment of advanced stage MFs and has response rates of 29–74% [32,33]. IFNα can be used in combination with PUVA therapy, which yields a high response rate. Bexarotene capsules are a systemic retinoid treatment that had a 45% response rate in multinational phase II and III clinical trials [34]. The most common side effects included hypertriglyceridemia, hypercholesterolemia, central hypothyroidism, and leukopenia, which required additional treatment [34]. Bexarotene can also be used in combination with PUVA, IFNα, and ECP in patients with advanced and refractory disease. Extracorporeal photopheresis (ECP) is an immunomodulating procedure that is used for the treatment of MF/SS. It has demonstrated an overall response rate of 55.7% but remains controversial in treating patients with patch, plaque, or tumor stages (stage IA to IIB) [35]. Histone deacetylase (HDAC) inhibitors aim to restore expression of tumor suppressors and cell cycle regulatory genes. Vorinostat is an HDAC inhibitor that is approved for the treatment of CTCL stage 1B or higher. In a phase II trial, vorinostat demonstrated an overall response rate of 24.2% and almost half the patients experienced pruritus relief, improving the quality of life [36]. Romidepsin is another HDAC inhibitor approved for treatment of advanced CTCL. In two phase II trials, the overall response rate was 33–34% and showed prolonged clinical response [37]. Mogamulizumab and brentuximab vedotin are systemic antibody treatments that have been approved for the treatment of CTCL. They have shown an overall response rate of 35% and 56%, respectively, and are two treatments that will be discussed further [38,39]. Chemotherapy is a treatment option that is reserved for rapidly progressing diseases but has not been shown to improve survival or remissions and risks often outweighs benefits. Immunotherapeutic and biological therapies are better tolerated.

4. Market review

There are a number of emerging treatments that have completed phase I, II, or III clinical trials. Mogamulizumab and brentuximab vedotin (BV) are two systemic antibody treatments that are FDA approved for the treatment of CTCL. Pembrolizumab, durvalumab, anti-CD47 inhibitors, antagomiR-155 (cobomarsen, MRG-106), and the IL-2 peptide inhibitor BNZ-1 are emerging treatments that are currently or have been evaluated in Phase I/II clinical trials.

4.1. Mogamulizumab

Mogamulizumab is a glycoengineered IgG1k monoclonal antibody targeting transmembrane chemokine receptor type 4 CCR4 and is presented as a novel treatment for CTCL [38]. Chemokines play a role in leukocyte trafficking and chemokine receptor CCR4 is involved in skin-homing T cells. The CCR4 ligand is TARC/CCL17 and the CCR4-TARC/CCL17 complex is involved in the extravasation of T cells into the skin [13]. CCR4 is expressed on T lymphocytes in ATLL, CTCL, and PTCL. Mogamulizumab binds to the N terminal domain of CCR4 causing antibody-dependent cellular cytotoxicity [40]. In the MAVORIC phase III clinical trial, 370 patients with relapsed MF or SS received either mogamulizumab or vorinostat, an FDA approved treatment for the disease. Patients received 1.0 mg/kg of mogamulizumab or 400 mg of vorinostat in each 28 day treatment cycle for up to 12 months or until progression. Median treatment exposure was 170 days and 84 days for mogamulizumab and vorinostat, respectively [41]. Mogamulizumab showed a 35% best overall response rate compared to the 6% best overall response rate of vorinostat. The most serious adverse side effects observed with mogamulizumab were pyrexia and cellulitis in 4% and 3% of patients, respectively, [41]. Other side effects also included infusion-related reactions, diarrhea, fatigue, and drug rash, which was the most frequent adverse event leading to discontinuation [38]. However, more frequent and severe adverse side effects were observed in patients in the vorinostat treatment group. Two patients who received mogamulizumab died of treatment-related adverse effects of sepsis and polymyositis, whereas three of the treatment-related deaths in vorinostat patients were due to pulmonary embolism and bronchopneumonia [41]. The trial showed that mogamulizumab was superior to vorinostat in the proportion of patients who achieved an overall response. Mogamulizumab received Pharmaceutical and Medical Devices Agency (PMDA) approval in Japan in 2014, European Medicines Agency (EMA) approval, and US FDA approval in 2018 for treatment of CTCL patients who have received a systemic therapy prior [42]. Notably, post-approval insights reveal that drug eruptions, now defined as mogamulizumab-associated rash (MAR), are the most common adverse event reported; however, the clinicopathologic nature of these eruptions remains unclear but may be related to depletion of FOXP3⁺CCR4⁺ regulatory T cells [43]. MAR can clinically mimic CTCL lesions and may occur more often in patients with clinical responses, highlighting the need for clinicians to rule out progressive disease and work-up that includes skin biopsies, flow cytometry studies for circulating Sezary cells and TCR sequencing in skin and blood.

4.2. Brentuximab vedotin

Brentuximab vedotin (BV) is a CD30 targeting antibody conjugated with monomethyl auristatin E (MMAE) by a protease-cleavage linker now approved for the treatment of CD30 expressing CTCL [44]. It is a membrane glycoprotein that belongs to the tumor necrosis factor (TNF) receptor family that, when expressed, promotes cellular proliferation. In MF/SS lesions, a median of 14% of the lymphoid cells showed positive staining for CD30 [12]. When expressed, CD30 activates TNFR signaling, which activates the IκB kinase 2 and NF-κB pathway to promote cell proliferation and survival [45]. BV binds to the extracellular domain of CD30 and is internalized where MMAE is cleaved in the cytosol. MMAE is an inhibitor of microtubule polymerization by binding to tubulin and inducing cell cycle arrest and apoptosis in CD30 expressing lymphoma cells [45]. In the phase 3 ALCANZA clinical trial, 131 patients with CD30 positive MF or primary cutaneous anaplastic large-cell lymphoma who failed previous treatments were assigned to either the BV or physician’s choice group. Patients received intravenous BV 1.8 mg/kg once every 3 weeks, for up to 16 3-week cycles, or physician’s choice (oral methotrexate 5–50 mg once per week or oral bexarotene 300 mg/m² once per day) for up to 48 weeks [39]. Patients in the brentuximab vedotin group had a global response rate of 56.3% compared to the response rate of 12.5% in the physician’s choice group after 22.9 months [39]. Peripheral neuropathy was the most common adverse event observed and was seen in 67% of patients in the BV group and 6% of patients in the physician’s choice group. In a phase II study, MF and SS patients with variable CD30 expression were treated with brentuximab vedotin, and results were favorable with overall global response in 70% of patients [44]. The results of these studies indicate that brentuximab vedotin is a compelling treatment option for both MF and SS patients. In 2017, brentuximab vedotin gained U.S. FDA approval for treatment of CTCL.

5. Current research goals and scientific rationale

The current goal is to develop new biologics and immunotherapies based on precision medicine. In development, there are treatments involving miR inhibitors, immune checkpoint inhibitors, peptide inhibitors, and CAR-T therapy. There are a number of treatments such cobomarsen (MRG-106), pembrolizumab, durvalumab, BNZ-1, and TTI-621 that are in ongoing clinical trials.

5.1. Cobomarsen (MRG-106)

Dysregulation of miR is involved in the CTCL pathogenesis. miR-155 is an identified oncogenic miR in CTCL that is overexpressed [46]. In CTCL, miR-155 promotes tumorigenesis through the JAK/STAT5, MAPK/ERK, and PI3K/AKT pathways [47]. STAT5 transcription factor becomes constitutively active, which induces miR-155 expression. miR-155 then represses the promoter region of the tumor suppressor SATB1 to enhance cytokine expression and inhibits STAT4 [47]. miR-155 also targets tumor suppressors JARID2, PDC4, ZNF652, SMAD5, and ARID2 resulting in increased tumor invasion, proliferation, and survival [48]. miRseq analysis has shown the overexpression of miRs −21, −130, −155 which demonstrates epigenetic regulation of PD-L1 in CTCL [49,50]. PD-L1 is part of an oncogenic PI3K/Akt pathway and is overexpressed in CTCL. There are multiple treatments in development to target miR-155. Cobomarsen (MRG-106) is an oligonucleotide inhibitor of miR-155 and was evaluated in a phase 1 clinical trial for CTCL. In this phase I study with 24 patients, administration of weekly or biweekly doses of MRG-106 via subcutaneous injection or IV infusion (300–900 mg/dose) and intralesional injection (75 mg/dose) yielded positive results in 95% of the subjects [51]. Subjects showed improvement in individually treated lesions or total skin disease measured by an improvement in modified Severity Weighted Assessment Tool (mSWAT) scores [51]. The drug was well tolerated with 48 drug related adverse events of grade 1 or 2 [51]. There was one adverse event of worsening grade 3 pruritus due to dose-limiting toxicity [51]. T cell clonality decreased with intralesional injection of MRG-106 post treatment. Patients exhibited on average a 55% reduction in their Composite Assessment of Index Lesion Severity (CAILS) score and improved histological findings [52]. Fifty percent of the patients reached a PR of a 50% reduction in mSWAT score, with greater benefit seen in patients who underwent >1 cycle [51]. This early data is encouraging to support continued investigation of cobomarsen in MF patients.

5.2. Immune checkpoint inhibitors

There are multiple therapeutics in development that target immune checkpoint inhibitors to combat T cell exhaustion. Pembrolizumab and durvalumab target the PD1 and PD-L1 pathways, respectively. TTI-621 (soluble signal regulatory protein alpha linked to the Fc region of IgG1) targets CD47.

5.2.1. Pembrolizumab

PD1 impairs T cell functions and is expressed on malignant and nonmalignant T cells in the tumor microenvironment of MF/SS [53]. PD1 and PD-L1 are immune checkpoint inhibitors. Programmed cell death protein 1 (PD1) is a transmembrane glycoprotein and contains a inhibitory tyrosine-based switch motif (ITSM) that is important for expressing the immune suppressive function in T cells [54]. PD-L1 is the ligand of PD1, and they interact in the tumor microenvironment [54]. Interaction between PD1 and PD-L1 results in phosphorylation of the tyrosine residues in the ITSM structure domain of PD1 that leads to phosphorylation of downstream proteins [54]. This results in inhibition of downstream signaling, T-cell functions resulting in T-cell exhaustion enabling tumor cells to evade T-cell immune surveillance [54]. PD1 ligation to its ligand PD-L1, expressed by immune infiltrating cells within the tumor microenvironment, can lead to immune escape of tumor cells and impairment of anti-tumor responses. Immune checkpoint inhibitors act by targeting exhausted T cells, thereby enhancing T cell-mediated anti-tumor responses. Pembrolizumab is a humanized monoclonal immunoglobulin (Ig) G4 antibody against PD1. In a recent phase 2 clinical CITN trial, pembrolizumab at a dose of 2 mg/kg was administered to 24 patients with advanced stage MF or SS every 3 weeks for up to 24 months [53]. Responses were measured with an objective response rate (ORR) of 38% (9 patients) including CR in 8% (2 patients). Notably, six of the 9 responding MF/SS patients had 90% improvement in mSWAT scores [53,55]. No grade 4 or 5 adverse events were noted. Cutaneous rashes and flares were the most common immune-related adverse events (irAE). Fourteen patients discontinued due to disease progression (seven patients), immune-related adverse events (three patients), and other unrelated adverse events (four patients) [55]. All irAEs resolved after discontinuation of treatment. Fifty-three percent of SS patients experienced worsened erythema, pruritus, and peripheral edema initially and were managed with supportive care. This flare is thought to be linked to the high expression of PD1 on Sézary cells and linked to cytokine release [55]. The results highlight that pembrolizumab is promising as a therapeutic treatment for relapsed MF and SS with durable responses and a favorable toxicity profile.

5.2.2. Durvalumab

Durvalumab is a human monoclonal antibody with high affinity for PD-L1, targeting T cells to reverse T cell exhaustion. PD1 and PD-L1 are highly expressed in tumor cells and work to inhibit the host’s antitumor activity. Durvalumab works to restore an anti-tumor response. A phase 1 study looked at administering durvalumab in combination with lenalidomide, an oral immunomodulatory drug in CTCL patients. Ten patients received a fixed dose of 1500 mg of durvalumab and a dose escalation of lenalidomide over 3 cycles. Preliminary results indicated low levels of PD-L1, with treatment showing it has significant clinical activity in treating CTCL [56]. Four patients in the trial showed improvement of skin disease, with two patients achieving a partial response of >90% improvement of skin disease by mSWAT [57]. No serious adverse events were observed, with the most frequently reported adverse events being fatigue, skin pain, chills, and leukopenia [56]. All other treatment-related adverse events were grade 1/2 severity. The treatment was well tolerated with low toxicity. The combination of durvalumab and lenalidomide is of benefit since it showed significant clinical activity in treating CTCL. Lenalidomide is an ideal candidate to use on immune checkpoint therapy because it has shown activity in CTCL, and has a pleiotropic effect on immune cells in the tumor microenvironment [58]. Patients with advanced and refractory CTCL stage IB-IVB were treated with lenalidomide monotherapy in a phase II clinical trial and results showed good clinical activity and safety profile [58]. Durvalumab and lenalidomide in combination may enhance immune checkpoint blockade induced immune response [57]. Phase II randomized trials evaluating durvalumab with lenalidomide have begun.

5.2.3. TTI-621

TTI-621 is a therapeutic treatment that targets CD47 by binding to SIRPα. A new therapy utilizing the immune checkpoint inhibitor TTI-621 (SIRPα-IgG1 Fc), a recombinant soluble fusion protein consisting of the CD47-binding domain of human SIRPα and the Fc region of human IgG1, targets the innate immune checkpoint CD47 to block the ‘do not eat’ macrophage phagocytosis signal by engaging macrophage Fcγ receptors with IgG1 Fc to promote phagocytosis and antitumor activity [16,59]. A phase I trial administered intratumoral injections of TTI-621 (1 mg/3 mg/10 mg) sequentially or in expansion cohorts enrolled 35 patients with relapsed or refractory MF/SS [60]. The most common adverse events were fatigue, chills, and decreased appetite, with all treatment-related adverse events being grade 1/2 in severity [59]. There was no dose limiting toxicity observed and the maximally assessed regimen was used [60]. The most common adverse events were chills, injection site pain, and fatigue in 29%, 26% and 23% of patients, respectively, [60]. There were no treatment-related adverse events that were grade 3 or higher and no treatment-related deaths [60]. Initial results of the study were promising with patients exhibiting a decrease in tumor size and/or decreased circulating Sézary cells and one patient achieving a complete response [59]. There was a reduction in Composite Assessment of Index Lesion Severity (CAILS) scores in 90% of the patients [60]. This was an important therapeutic signal that is now being further evaluated in clinical trials that are combining anti-CD47 antibodies with other targeted agents and immune modifiers.

5.3. BNZ-1

BNZ-1 is a pegylated peptide antagonist that binds to the common gamma-chain signaling receptor for cytokines IL-2, IL-9, and IL-15 [61]. BNZ-1 which upon binding, blocks the downstream signaling pathways of IL-2, IL-9, and IL-15. From this, IL-2 and IL-15 will be inhibited to block tumor cells proliferation and IL-2 and IL-9 inhibition decreases regulatory T cells that impede in anti-lymphoma response [61]. Inhibition of these three cytokines can provide a therapeutic benefit for CTCL patients by blocking cytokine-driven propagation and survival of tumor cells, lower activity of regulatory T-cells, and anti-inflammation. In a phase 1/2 study, 15 refractory patients were enrolled in cohorts and received a dose of 0.5/1/2/4 mg/kg of weekly intravenous doses of BNZ-1. Of the 15, 9 patients were then enrolled in a 3 month extension phase of BNZ-1 dosing, with 3 patients receiving long-term extensions upon response [61]. Dosing was determined to be best at 2 mg/kg. One patient achieved a complete response, eleven (58%) achieved a partial response, and 7 patients showed stable disease as measured by mSWAT and global response score [61]. The treatment was well tolerated with no serious treatment-related adverse events, and no toxicity suggesting BNZ-1 may provide a novel treatment option for CTCL patients [61].

5.4. Anti-KIR3DL2

KIR3DL expression is upregulated in all subtypes of CTCL. IP4102 is an anti-KIR3DL2 monoclonal antibody that depletes KIR3DL2 expressing cells by antibody-dependent cell cytotoxicity [62]. In a phase I study, IPH4102 is being evaluated in patients with relapsed/refractory CTCL. Forty-four patients were treated with no dose limiting toxicity [25]. The most common adverse events were peripheral edema (27% of the patients) and fatigue (20% of the patients) all of which were grade 1 and 2 [25]. Seven percent of the patients experienced lymphopenia that was a grade 3 adverse event [25]. The drug was well tolerated, with a global overall response rate of 16 of 44 patients [25]. Multi-cohort phase II trials are currently underway.

5.5. P13 K, SYK/JAK inhibitors

Phosphatidylinositol 3-kinase (P13 K) is a cellular signaling protein, with downstream processes driving oncogenic processes. The δ and γ isoforms are expressed in cells of hematopoietic origin, so they are a target for peripheral and cutaneous T cell lymphoma [63]. Tenalisib (RP6530) is a novel, oral dual PI3K δ/γ inhibitor that was evaluated in phase I/II clinical trials. The overall response rate in 35 patients was 45.7% with downregulation of CD30, IL-31, and IL-32α [64]. Two dose-limiting toxicities of 800 mg were observed and treatment emergent adverse events included fatigue (45%) and transaminase elevations (33%) [64]. Tenalisib shows promising clinical activity and phase I/II combination studies with romidepsin are underway.

SYK and JAK signaling pathways are important to the pathogenesis of PTCL and CTCL. Cerdulatinib is a small molecule reversible ATP competitive inhibitor of SYK/JAK and was evaluated in a phase IIa study [65]. CTCL and PTCL patients were treated with cerdulatinib 30 mg orally BID. The overall response rate was 35%, but the ORR was higher in MF patients at 45%, with 9% achieving CR, whereas in SS patients the ORR was 17% [65]. Treatment emergent grade 3+ adverse events were lipase increase (21%), amylase increase (18%), diarrhea (8%), neutropenia (8%), anemia (7%), and fatigue (6%) [65]. Overall, cerdulatinib showed good tolerability and promising clinical activity that will be further evaluated in trials.

5.6. Skin directed investigational therapies

Skin-directed therapies are a treatment option that have negligible systemic effects. Remetinostat is a topical HDAC inhibitor applied to cutaneous lesions. In a phase II study, 60 patients with stage IA-IIA MF were randomized into three dosage groups and clinically meaningful reduction in pruritis (CMRP) was measured, which is defined as a ≥ 30 mm decrease for 2 consecutive visits [66]. The CRMP was 37.5%, 50%, and 80% for the three treatment groups of 1% QD, 0.5% BID, and 1% BID dosage groups, respectively, [66]. This data demonstrates potential benefit of topical remetinostat in pruritis reduction for patients with MF.

Hypericin is a photodynamic agent that induces apoptosis in malignant B and T lymphocytes and is an emerging topical treatment in the treatment of CTCL. In a phase II study, lesions were treated twice weekly for 6 weeks with topical synthetic hypericin, or a placebo followed by visual light [67]. Results showed an in improvement in skin lesions in patients on hypericin therapy compared to no improvement on the placebo [67]. Emerging data from a phase III double-blind clinical trial (FLASH study) are promising.

6. Competitive environment

The current market for development is very competitive as CTCL is a rare disease. Many of the treatments on the market or in development are monoclonal antibodies, but targets vary. Mogamulizumab, is a defucosylated humanized monoclonal antibody that targets CCR4. It was the FDA approved in 2018 for the treatment of CTCL and approved in Japan for ATCLL and CTCL. Brentuximab vedotin, a humanized monoclonal antibody, is another therapeutic that is already approved to be on the market. It has been FDA approved for CD30 expressing MF in 2017. Cobomarsen (MRG-106) is an oligonucleotide inhibitor of miR-155. The FDA has granted Cobomarsen orphan drug designation for the treatment of T-cell lymphoma. Currently, it is in phase II clinical trials for CTCL and phase I clinical trials for adult T-cell leukemia/lymphoma (ATLL). Pembrolizumab, a PD-1 inhibitor, is in phase II clinical trials for treatment of CTCL. Durvalumab is another cell checkpoint inhibitor targeting PD-L1 that is in phase II clinical trials for treatment of CTCL. TTI-621 is a recombinant fusion protein targeting CD47 and is in phase I clinical trials for treatment of CTCL. BNZ-1 is a pegylated peptide inhibitor that is in phase III clinical trials for the treatment of CTCL. Table 2 summarizes treatments that are approved and in development.

Table 2.

Summary of therapeutics on the market and in development for CTCL.

Compound	Company	Structure	Indication	Stage of Development	Mechanism of Action
Mogamulizumab (Poteligeo)	Kyowa Kirin	Defucosylated, humanized monoclonal antibody against CCR4	CTCL  ATLL  PTCL	FDA Approved in US for CTCL  ATL in Japan	CCR4 receptor antagonist
Brentuximab Vedotin (Adcetris)	Seattle Genetics, Inc	Humanized IgG1 monoclonal antibody	ASCT  ALCL  MF  PTCL	FDA Approved	CD30 antagonist
MRG-106 (Cobomarsen)	miRagen Therapeutics	Synthetic locked nucleic acid-modified inhibitor	CTCL  MF  ATLL	Phase II clinical trial	Oligonucleotide inhibitor to miR-155
Pembrolizumab (Keytruda)	Merck & Co., Inc	Humanized IgG4 monoclonal antibody	CTCL  PTCL	Phase II clinical trial	PD-1 inhibitor
Durvalumab (Imfinzi)	AstraZeneca	Humanized IgG1 monoclonal antibody	CTCL	Phase II clinical trial	Target PD-L1
TTI-621	Trillium Therapeutics Inc	Recombinant fusion protein	CTCL, PTCL	Phase I clinical trial	Binds SIRPα to block interaction with CD47
BNZ-1	Bioniz Therapeutics	Pegylated peptide antagonist	CTCL	Phase III clinical trial	Inhibits IL-2, IL-9, IL-15
IPH4102	Innate Pharma	Monoclonal antibody	CTCL	Phase II clinical trial	Target KIR3DL2

CCR4, chemokine receptor 4; CTCL, cutaneous T cell lymphoma; ATLL, adult T cell leukemia/lymphoma; PTCL, peripheral T cell lymphoma; ASCT, autologous stem cell transplant; ALCL anaplastic large cell lymphoma; MF, mycosis fungoides; SIRPα, signal regulatory protein alpha

7. Potential development issues

There have been major advances to the treatment of CTCL with the approval of mogamulizumab and brentuximab vedotin, but not without challenges. BV has significant neurotoxicity and is less tolerable over time. However, it is effective in patients with 5% CD30 expression and above with a good response rate, making BV an option for patients who have even minimal CD30 expression. It is still unclear if response correlates with the degree of CD30 expression. Mogamulizumab is more effective in erythrodermic patients and appears to have higher efficacy than in trials, but patients with transformed disease were excluded from the trial, and it is not indicated for the treatment of transformed MF. The major adverse events seen in the clinical trials were pyrexia, cellulitis, and pneumonia. There are ongoing maintenance trials with monthly treatment underway. Despite these major advances, neither have been shown to improve survival.

In a study examining the efficacy of MRG-106, activity was specific to miR-155 inhibition and demonstrated cell proliferation inhibition and apoptosis induction in MF cells [68]. It is comparable to bexarotene, a commonly prescribed systemic therapy, in its ability to inhibit cell proliferation and unlike bexarotene, MRG-106 is able to induce apoptosis. The drug was well tolerated, with adverse events being grade 1 or 2 pruritis [51].

Cell checkpoint inhibitors such as pembrolizumab, durvalumab, and TTI-621 show promising results in clinical trials. With pembrolizumab, more than half of the patients initially experienced worsened flares and 14 of the 24 patients in the trial discontinued due to disease progression or adverse events. Durvalumab was well tolerated in the trials with a high overall response rate with improved mSWAT scores. Additionally, toxicity was low and adverse events were low grade in severity. Similarly, patients in the TTI-621 trial experienced decreased tumor size and the drug was well tolerated. Adverse events were low grade in severity, and toxicity was low.

There are some unique challenges when it comes to developing CAR-T therapy for CTCL since malignant and healthy T cells display the same markers making it difficult to develop a targeted treatment. Three potential hurdles are T cell aplasia, fratricide, and product contamination. Possible solutions include targeting T cell subsets, short-lived CAR T cells, gene editing, targeting downregulated antigens, and using NK cells [69].

8. Conclusion

There are many new biological treatments that are in development for CTCL. The approval of mogamulizumab and BV is exciting by providing targeted treatment options that have good outcomes. Pembrolizumab, durvalumab, MRG-106, BNZ-1, and TTI-621 are still in clinical trials, but preliminary data is promising. As these treatments continue to go through clinical trials, it will pave the way for improved therapeutic options for patients with severe and relapsed CTCL to successfully treat disease and increase quality of life.

9. Expert opinion

The standard treatment of corticosteroids, phototherapy, and retinoids are a valid and effective treatment that should still be first line of treatment in patients with early-stage disease. Similarly, the standard systemic treatments of retinoids/rexinoids, interferons, ECP, HDAC inhibitors, and combination therapy should continue to be utilized as patients progress toward more advanced stages. Immunotherapies have already been introduced to the market and are an option for some patients. The therapeutics discussed in this review, such as mogamulizumab, BV, pembrolizumab, durvalumab, TTI-621, BNZ-1, and MRG-106 are aimed for patients who have relapsed or refractory disease and have already failed multiple treatment options. Antibodies have reached the market and are approved for CTCL providing valuable options. Mogamulizumab is a good option for erythrodermic patients and clinical results are promising. For patients with an elevated CD30 expression, brentuximab vedotin is a viable treatment option, though it does have severe side effects primarily neurotoxicity. Immune checkpoint inhibitors have reached the landscape and have provided treatment options. Similarly, novel treatments like oligonucleotides and antagomirs, though in the early stages of development, hold promise. MRG-106, pembrolizumab, durvalumab, BNZ-1, and TTI-621 are still in clinical trials but have therapeutic potential for patients who have advanced refractory disease. So far, immune checkpoint inhibitors have shown long-lasting responses, but not all patients respond. It is unknown why responses vary. None of these treatments have demonstrated long-term remissions, and thus further studies on combinations are needed. Despite this, all these therapeutics are exciting and novel options for the treatment of CTCL. Understanding the mechanisms of action on tumor cells and the TME will help to choose patients that likely show benefit, improve patient quality of life, and reduce potential toxicities.